Abstract
Context
Denosumab inhibits the receptor activator of nuclear factor κ-Β ligand, an immune system modulator. Safety endpoints including risk for infections were assessed as secondary outcomes ...in randomized controlled trials (RCTs) of the drug.
Objective
To assess the risk of serious adverse events of infections (SAEI) in denosumab-treated patients.
Data Sources
PubMed and Cochrane Central Register of Controlled Trials were searched up to May 27, 2019.
Study Selection
All RCTs of denosumab (60 mg every 6 months) versus any comparator were included. We excluded trials in cancer patients for prevention of skeletal-related events.
Data Extraction
Two reviewers independently applied selection criteria and extracted the data. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a fixed effect model. Sensitivity analysis was based on risk of bias.
Data Synthesis
Thirty-three studies (22 253 patients) were included. There was a higher incidence of SAEI during denosumab treatment versus any comparator (RR, 1.21; 95% CI, 1.04-1.40; I2 = 0%), mainly of ear, nose, and throat (RR, 2.66; 95% CI, 1.20-5.91) and gastrointestinal origin (RR, 1.43; 95% CI, 1.02-2.01). RR was similar in a sensitivity analysis based on adequate allocation concealment. The RR of any infection (RR, 1.03; 95% CI, 0.99-1.06) and infection-related mortality (RR, 0.50; 95% CI, 0.20-1.23) was comparable between groups.
Conclusions
A higher incidence of SAEI is demonstrated during treatment with denosumab in an osteoporosis dose. Nevertheless, the overall risk for any infection or related mortality is similar to comparator groups. These findings merit consideration before therapy initiation.
•Patients treated with dual antiplatelet therapy that includes ticagrelor have a 64% lower risk of gram-positive infection during the first year following hospitalization compared with patients ...treated with dual antiplatelet therapy treatment that includes clopidogrel.•This observed association is bolstered by the fact that gram-positive infection risk is comparable between ticagrelor and clopidogrel treated patients after discontinuation of dual antiplatelet therapy.•Treatment with ticagrelor was not associated with a reduced risk of gram-negative infections during the first year following acute coronary syndrome hospitalization, a finding compatible with previous in vitro studies.
In light of recent studies describing the antibacterial properties of ticagrelor, the association between treatment with ticagrelor and subsequent risk for infection following acute coronary syndrome (ACS) is taking on increased importance. A single center, retrospective, matched cohort analysis was performed. All patients older than 30 years of age admitted between January 1, 2013 and November 1, 2019 for an ACS and discharged with dual antiplatelet therapy (DAPT) were included. The primary outcome was defined as hospital admissions due to infections likely caused by gram-positive bacteria up to 1 year following the ACS hospitalization. The base cohort included 3,909 patients. About 2,035 (52.1%) were treated with ticagrelor and 1,874 (47.9%) with clopidogrel. Patients treated with ticagrelor had a 64% lower risk of gram-positive infection during the first year following hospitalization after adjusting for demographic and co-morbidity factors compared with those treated with clopidogrel (hazard ratio HR, 0.36; 95% confidence interval CI, 0.21 to 0.61; p <0.001). In a cohort starting from 1 year (conclusion of DAPT period) and up to 3 years following ACS hospitalization, the risk of gram-positive infection was comparable in both groups (HR, 0.70; 95% CI, 0.41 to 1.19; p = 0.182). Treatment with ticagrelor was not associated with a reduced risk of gram-negative infections (HR, 0.48; 95% CI, 0.21 to 1.06; p = 0.07). In conclusion, DAPT regimen that includes aspirin and ticagrelor is associated with reduced risk of gram-positive infection compared with the combination of aspirin and clopidogrel.
Purpose. To evaluate the associations between metformin, insulin, statins, and levothyroxine and breast cancer characteristics and outcome. Methods. Retrospective chart review of patients treated in ...our institute for early estrogen receptor (ER) positive, human epidermal growth factor receptor 2 negative breast cancer, whose tumors were sent to Oncotype DX (ODX) analysis. Patients were grouped according to medications usage during the time of breast cancer diagnosis. Each group was compared to the rest of the study population. Results. The study cohort included 671 patients. Sixty (9.1%) patients were treated with metformin, 9 (1.4%) with insulin, 208 (31.7%) with statins, and 62 (9.4%) with levothyroxine. Patients treated with metformin had more intense ER stain ( p = 0.032 ) and a lower ODX recurrence score (RS) ( p = 0.035 ). Diagnosis of diabetes mellitus was also associated with lower ODX RS ( p = 0.014 ). Insulin usage was associated with a higher rate of angiolymphatic invasion ( p = 0.041 ), but lower Ki67% ( p = 0.017 ). Levothyroxine usage was associated with different histological subtype distribution ( p = 0.02 ). Extended levothyroxine usage was associated with lower ODX RS ( p = 0.005 ). Statin usage had no impact on tumor characteristics. Outcome was comparable in the studied subgroups. Conclusions. Common medications for metabolic disorders might be associated with breast cancer characteristics.
Changes in primary outcome and sample size measures after onset of patient accrual affects the scientific basis of evidence-based medicine. The FDA website was searched for trials supporting new ...hemato-oncology drug approvals from January 2010 to December 2017. Matching ClinicalTrials.gov entries were compared to identify modifications. Associated publications were reviewed for reporting of these changes. Of 69 included trials, five (7%) had post accrual modifications in primary outcome and 30 (43%) had modifications in planned sample size. Sample size was increased in 24 trials (median 66 patients, IQR 35-95, median relative increase of 40% from initial sample size) and was decreased in 6 trials (median 38 patients, IQR 27-60, median relative decrease of 25%). None of the primary outcome modifications and only 53% of the sample size modifications were reported in the related publications. Further improvement is warranted in order to achieve complete transparency in reporting landmark studies.
Abstract
Objectives
SLE is a multisystem autoimmune disorder known for its broad clinical spectrum. Recently, the European, British and Latin American rheumatology professional societies EULAR, ...British Society for Rheumatology (BSR) and Pan-American League of Associations of Rheumatology (PANLAR) published updated recommendations for SLE management. The objective of this study was to characterize the data supporting the updated recommendations, with the goal of highlighting areas that could benefit from additional high-quality research.
Methods
References were compiled from the recently published EULAR, BSR and PANLAR SLE treatment recommendations. Data collected from each study included publication year, treatment regimen, study design, sample size, inclusion and exclusion criteria and relevant SLE diagnostic criteria. Studies with less than 10 patients and those that did not specify the SLE diagnostic criteria used were excluded.
Results
Altogether, 250 studies were included in this study. The majority were prospective and retrospective cohorts (72%), with only a small percentage of randomized controlled trials (28%). The median (interquartile range) number of patients included was 37 (19–86). The revised ACR 1982 criteria were the most commonly used criteria for SLE diagnosis (52%), followed by the revised ACR criteria from 1997 (27%). Only a small proportion of studies included the use of disease activity scores when defining study population (15%).
Conclusion
Our study has indicated a scarcity of sufficiently powered high-quality research referenced in the recently published SLE treatment guidelines. Well-designed large-scale studies utilizing the updated 2019 SLE diagnostic criteria are needed to better inform healthcare professionals caring for patients with SLE.
Background
Glucagon-like peptide 1 receptor agonists (GLP1RAs) are used in the treatment of diabetes and obesity. Their slowing effect of gastric emptying might change oral drug absorption, ...potentially affecting pharmacokinetics, particularly in the case of medications with a narrow therapeutic index.
Purpose
The purpose of this systematic review is to summarize data on drug-drug interactions between GLP1RAs and oral drugs.
Data Sources
The PubMed and EMBASE databases were searched up to November, 1st 2023.
Study Selection
We selected pharmacokinetic studies of any injectable GLP1RA given with an oral medication, and product prescribing sheets reporting data without access to the original study.
Data Extraction
Two authors independently extracted the data.
Data Synthesis
Twenty-two reports and six prescribing sheets were included. Treatment with GLP1RAs resulted in unaffected or reduced
C
max
and delayed
t
max
of drugs with high solubility and permeability (warfarin, contraceptive pills, acetaminophen), drugs with high solubility and low permeability (angiotensin converting enzyme inhibitors), drugs with low solubility and high permeability (statins) and drugs with low solubility and permeability (digoxin). However, the use of GLP1RAs did not exert clinically significant changes in the AUC or differences in clinically relevant endpoints.
Limitations
The major limitations of the studies that are included in this systematic review are the enrollment of healthy subjects and insufficient data in conditions that might affect pharmacokinetics (e.g., kidney dysfunction).
Conclusions
To conclude, reduced
C
max
and delayed
t
max
of drugs co-administered with GLP1RAs are consistent with the known delayed gastric output by the latter. Nevertheless, the overall drug exposure was not considered clinically significant. Dose adjustments are probably not required for simultaneous use of GLP1RAs with oral medications. Still, results should be carefully generalized to cases of background kidney dysfunction or when using drugs with narrow therapeutic index. The study is registered in PROSPERO:
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022332339
.
As the treatment for metastatic breast cancer (MBC) often includes sequential lines of therapy, data on post-protocol treatment in clinical trials are valuable in the assessment of long-term ...outcomes. The objective of this study was to assess the reported data on post-protocol therapy in clinical trials supporting US Food and Drug Administration (FDA) approval of drugs for MBC.
All initial and subsequent publications related to FDA approved indications for MBC between January 2000 and February 2023 were identified. Collected data included study design, patients' characteristics and whether reporting on post-protocol therapy was available. Differences in study design and population between studies with and without data on post-protocol therapy were evaluated.
Forty-one indications for MBC were identified. Data were evaluated from 249 publications or abstracts, comprising 20,152 patients. Reporting of post-protocol therapy was available for 22 (53.7 %) indications. Reported data were often incomplete. Reporting has not improved over time with reported data in 50 % and 55.2 % studies between 2000 and 2010 and 2011-2023 (p value for the difference = 1.0), respectively. Studies with OS as their primary endpoints were associated with significantly higher reporting of post-protocol therapy, (p = 0.02). Other characteristics of study design and population were comparable between studies with and without data on post-protocol therapy.
Data on post-protocol therapy in trials supporting FDA approval of drugs for MBC are available for only half of the indications. As subsequent lines of therapy may have a crucial role in patients' outcome, post-protocol reporting should be included in the regulatory submission and be made available publicly.
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